PROJECT SUMMARY: The project goal is to identify genes that modify tau pathogenicity. Two approaches will be used, both based on unbiased screens, and thus both can potentially reveal new features of taumediated toxicity. The first approach is to use human genetics to identify genes that contribute to risk for frontotemporal lobar dementia (FTLD). Previously we performed a genome-wide association study (GWAS) using progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) cases, both of which are FTLDs. Five genes were identified: MAPT, NELL2, the FAM76B/translokin/MTMR2 gene cluster, MOBP, and STX6. We will follow up on these loci, performing further human genetics studies and functional analysis. The second approach for identifying modifying loci is to use C. elegans as a tauopathy model. We will identify genes that suppress the toxic effects of tau in C. elegans and translate the finding into a mammalian model system. The Specific Aims are: 1) Follow-up the PSP/CBD GWAS, by collecting additional PSP/CBD subjects, performing dense SNP mapping of the susceptibility genes, examine the expression of the PSP/CBD susceptibility genes with respect to genotype, and test these susceptibility genes in our C. elegans model. 2) Sequence genes involved in FTLD related neurodegenerative diseases. Subjects to be sequenced will primarily be FTLD cases. These experiments will identify rare variants that cause FTLD. 3) Identify new tau toxicity modifiers in our C. elegans model. 4) Generate a mouse knockout of an orthologue of a previously identified C. elegans suppressor gene (SUT2). These mice, null for the mammalian gene (mSUT2) will be crossed with a tau transgenic mouse PSI9 that develops a tauopathy-related phenotype. These experiments will determine if loss of mSUT2 can suppress tauopathy as SUT2 does in C. elegans. This project will identify genes that cause/modify tau toxicity, which is the key to undestanding FTLD. These findings will also be important to Alzheimer's disease, a disorder that also has prominent tau pathology.